Grant Number:	5R01CA216354-05 Interpret this number
Primary Investigator:	Yasui, Yutaka
Organization:	St. Jude Children'S Research Hospital
Project Title:	Late Effects Prediction Using Clinical Phenotypes and Whole Genome Sequencing
Fiscal Year:	2021

With the remarkable improvement in cure rates of childhood cancer over the last several decades, over 80% of children in the U.S. with cancer today become long-term (5+ years) survivors. This growing population of survivors, currently over 400,000 nationwide, reflects a highly vulnerable group of individuals with a high probability of experiencing adverse health-related and quality-of-life outcomes. To provide proper care for this population and inform the design of future treatment regimens, it is imperative to gain sound understanding of their long-term morbidity/mortality associated with specific therapeutic exposures, genetic profiles, sex and other demographic characteristics, and co-morbid medical conditions. Growing body of published literature exists addressing specific adverse outcomes and their associations with specific therapeutic exposures. While these association studies have provided key evidence utilized to develop follow-up care guidelines such as those of Children's Oncology Group, recognizing “associations” (differences) is not sufficient for provision of individually-tailored follow-up care. Ability to “predict” (prognose) is required to expand the impact of survivorship-based research and allow translation of observational research toward individualized-precision survivorship care. Capitalizing on existing strengths of the well-established and highly productive survivorship- based research program at St. Jude Children's Research Hospital, with currently available late effects outcomes data from direct clinical assessments and whole genome sequencing of germline DNA, the proposed project will apply state-of-the-art methods to construct and independently validate outcome-specific prediction models, based on a phenotype pathway/modeling framework for each outcome, incorporating genetic predictors with laboratory-based functional validation. We will undertake an aggressive program of survivorship focused research to address NCI's Provocative Question PPQ-7: How can prediction models be developed and used to identify patients at highest risk of treatment-related complications? By not restricting the proposed research to a small number of late effects outcomes or a specific diagnosis of childhood cancer, our aims are ambitiously set to extensively contribute to and meaningfully impact clinical practice. Our specific aims are to: (1) build individual-risk prediction models that have clinically-appropriate degrees of precision, for the following 11 late effects outcomes: meningioma; basal cell carcinoma; multiple subsequent neoplasms; cardiomyopathy; obstructive lung disease; restrictive lung disease; diabetes mellitus; oligo/azoospermia; primary hypogonadism; memory deficit; and executive function deficit; (2) validate them with independent validation cohorts; and (3) functionally/biologically validate the genetic elements in the risk prediction models. Upon completion of (1)-(3), we extend the model building, validation, and functional/biological validation work to 9 additional late effects: stroke; arrhythmia; growth hormone deficiency; hypothyroidism; central hypogonadism; processing speed deficits; attention deficits; hearing loss; and bone mineral density deficits.




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Serum Proteins Predict Treatment-Related Cardiomyopathy Among Survivors of Childhood Cancer.
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Correction: St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors.
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Statistical Analysis of Self-Reported Health Conditions in Cohort Studies: Handling of Missing Onset Age.
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The burden of cardiovascular disease and risk for subsequent major adverse cardiovascular events in survivors of childhood cancer: a prospective, longitudinal analysis from the St Jude Lifetime Cohort Study.
Authors: Hammoud R.A. , Liu Q. , Dixon S.B. , Onerup A. , Mulrooney D.A. , Huang I.C. , Jefferies J.L. , Rhea I.B. , Ness K.K. , Ehrhardt M.J. , et al. .
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Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.
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St. Jude Survivorship Portal: sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors.
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Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy.
Authors: Ehrhardt M.J. , Liu Q. , Mulrooney D.A. , Rhea I.B. , Dixon S.B. , Lucas J.T. , Sapkota Y. , Shelton K. , Ness K.K. , Srivastava D.K. , et al. .
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Association analysis of self-reported outcomes with a validated subset.
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Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort.
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Refining the genetic risk of breast cancer with rare haplotypes and pattern mining.
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Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report.
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Trans-ancestral genetic study of diabetes mellitus risk in survivors of childhood cancer: a report from the St. Jude Lifetime Cohort and the Childhood Cancer Survivor Study.
Authors: Im C. , Neupane A. , Baedke J.L. , Delaney A. , Dixon S.B. , Chow E.J. , Mostoufi-Moab S. , Richard M.A. , Gramatges M.M. , Lupo P.J. , et al. .
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Development and Validation of a Prediction Model for Kidney Failure in Long-Term Survivors of Childhood Cancer.
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Dynamics of age- versus therapy-related clonal hematopoiesis in long-term survivors of pediatric cancer.
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Inference on the Genetic Architecture of Breast Cancer Risk.
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Genome-wide Analysis of Rare Haplotypes Associated with Breast Cancer Risk.
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Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.
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Underdiagnosis and Undertreatment of Modifiable Cardiovascular Risk Factors Among Survivors of Childhood Cancer.
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Leveraging therapy-specific polygenic risk scores to predict restrictive lung defects in childhood cancer survivors.
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A novel locus on 6p21.2 for cancer treatment-induced cardiac dysfunction among childhood cancer survivors.
Authors: Sapkota Y. , Ehrhardt M.J. , Qin N. , Wang Z. , Liu Q. , Qiu W. , Shelton K. , Shao Y. , Plyler E. , Mulder H.L. , et al. .
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Contribution of Genome-Wide Polygenic Score to Risk of Coronary Artery Disease in Childhood Cancer Survivors.
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Therapeutic and prognostic insights from the analysis of cancer mutational signatures.
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Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.
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Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.
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Genome-wide association studies reveal novel locus with sex-/therapy-specific fracture risk effects in childhood cancer survivors.
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Parallel repulsive logic regression with biological adjacency.
Authors: Yoneoka D. , Im C. , Yasui Y. .
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Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.
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Epigenetic Age Acceleration and Chronic Health Conditions among Adult Survivors of Childhood Cancer.
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A Novel Locus Predicts Spermatogenic Recovery among Childhood Cancer Survivors Exposed to Alkylating Agents.
Authors: Sapkota Y. , Wilson C.L. , Zaidi A.K. , Moon W. , Fon Tacer K. , Lu L. , Liu Q. , Baedke J. , Dhaduk R. , Wang Z. , et al. .
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Pathogenic Germline Mutations in DNA Repair Genes in Combination With Cancer Treatment Exposures and Risk of Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer.
Authors: Qin N. , Wang Z. , Liu Q. , Song N. , Wilson C.L. , Ehrhardt M.J. , Shelton K. , Easton J. , Mulder H. , Kennetz D. , et al. .
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Predicting acute ovarian failure in female survivors of childhood cancer: a cohort study in the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime Cohort (SJLIFE).
Authors: Clark R.A. , Mostoufi-Moab S. , Yasui Y. , Vu N.K. , Sklar C.A. , Motan T. , Brooke R.J. , Gibson T.M. , Oeffinger K.C. , Howell R.M. , et al. .
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Whole-genome sequencing of childhood cancer survivors treated with cranial radiation therapy identifies 5p15.33 locus for stroke: A report from the St. Jude Lifetime Cohort study.
Authors: Sapkota Y. , Cheung Y.T. , Moon W. , Shelton K. , Wilson C.L. , Wang Z. , Mulrooney D.A. , Zhang J. , Armstrong G.T. , Hudson M.M. , et al. .
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Genome-Wide Association Study in Irradiated Childhood Cancer Survivors Identifies HTR2A for Subsequent Basal Cell Carcinoma.
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Analysis of error profiles in deep next-generation sequencing data.
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Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE).
Authors: Wang Z. , Liu Q. , Wilson C.L. , Easton J. , Mulder H. , Chang T.C. , Rusch M.C. , Edmonson M.N. , Rice S.V. , Ehrhardt M.J. , et al. .
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A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.
Authors: Brooke R.J. , Im C. , Wilson C.L. , Krasin M.J. , Liu Q. , Li Z. , Sapkota Y. , Moon W. , Morton L.M. , Wu G. , et al. .
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Genome-wide search for higher order epistasis as modifiers of treatment effects on bone mineral density in childhood cancer survivors.
Authors: Im C. , Ness K.K. , Kaste S.C. , Chemaitilly W. , Moon W. , Sapkota Y. , Brooke R.J. , Hudson M.M. , Robison L.L. , Yasui Y. , et al. .
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The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE).
Authors: Bhakta N. , Liu Q. , Ness K.K. , Baassiri M. , Eissa H. , Yeo F. , Chemaitilly W. , Ehrhardt M.J. , Bass J. , Bishop M.W. , et al. .
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